Basic Concepts Flashcards
What is a locus?
Segment of DNA occupying a particular position or location on a chromosome
What are alleles?
Alternative variants of a gene
- Wild type or common allele: single prevailing allele present in the majority of individuals
- Other versions are variant of mutant alleles that differ from the wild-type because of the presence of a mutation
Define the following:
- Homozygous
- Heterozygous
- Compound heterozygote
- Homozygous: when a person has a pair of identical alleles at a locus
- Heterozygous (aka “carrier”): when a person has different alleles on both pairs of a chromosome
- Compound heterozygote (aka “double heterozygote”): 2 different mutant alleles of the same gene are present
What is hemizygous?
Male has an abnormal allele for a gene located on the X chromsome and there is no other copy of the gene (neither homozygous nor heterozygous)
Genotype vs. phenotype?
- Genotype: set of alleles that make up his/her genetic constitution; either collectively at all loci or more typically, at a single locus
- Phenotype: observable expression of a genotype as a morphological, clinical, cellular, or biochemical trait
- Can be normal or abnormal
How many genes do humans have?
- Chromosomes?
- About 20,000 genes
- 46 chromosomes (23 pairs)
Describe the following genetic disorder patterns:
- Single gene (Menelian)
- Chromosomal
- Multifactorial
in terms of:
- Prevalence
- Pattern of inheritance
- Risk to relatives
Single gene (Mendelian)
- Numerous though individually rare
- Clear pattern of inheritance
- High risk to relatives
Chromsomal
- Mostly rare
- No clear pattern of inheritance
- Usually low risk to relatives
Multifactorial
- Common disorders
- No clear pattern of inheritance
- Low/moderate risk to relatives
What is penetrance?
Percentage of relatives expressing the disorder to any degree, from the most trivial to the most severe
What are different types/expressions of penetrance? Examples?
Age dependent penetrance
- Huntington disease
Incomplete penetrance: not all mutation carriers will manifest the disorder during a natural lifespan
- Lynch syndrome
What is expressivity?
Variation in the severity of a disorder in individuals who have inherited the same disease alleles
What are the different types/expressions of expressivity?
- Interfamilial variation: difference in severity between families
- Intrafamilial variation: difference in severity within families carrying the same mutation
- E.g. tuberous sclerosis
What is mosaicism? Subtypes?
Somatic mosaicism:
- A new mutation arising at an early stage in embryogenesis causing a partial phenotype
- Ex) segmental NF1
Gonadal/germline mosaicism:
- A new mutation arising during oogenesis or spermatogenesis may cause no phenotype in the parent but can be transmitted to the offspring
Describe autosomal dominant inheritance
- Number of mutant alleles
- Chance of passing to offspring
- Features of inheritance pattern
- 1 mutant allele is sufficient to cause disease
- 50% chance of transmission with each pregnancy
Features:
- Vertical transmission
- Male-to-male transmission
- Affected males = affected females
What inheritance pattern is seen here?
Typical autosomal dominant
What inheritance pattern is seen here?
Non-penetrance of autosomal dominant
What inheritance pattern is seen here?
New mutation (of autosomal dominant)
What inheritance pattern is seen here?
Sex-limited expression (of autosomal dominant)
What inheritance pattern is seen here?
Gonadal mosaicism
Describe autosomal recessive inheritance
- Number of mutant alleles
- Features of inheritance pattern
- 2 mutant genes are required to cause disease
Features:
- Horizontal pattern of affected individuals
- Males and females equally affected
- Parents unaffected yet obligate carriers
- Child of affected persons is (at least) obligate carrier
What is the Lyon Hypothesis?
One X in female somatic cells undergoes random inactivation
Describe sex chromosome inheritance
- Males are hemizygous for genes on the X chromosome
- All daughters of affected males are carriers
- 50% of daughters of carrier females are carriers
- 50% of sons of carrier females are affected
- All sons of affected males are “normal”; there is no male-male transmission of X linked conditions!
Describe the mitochondrial genome
- Linear vs. circular
- Number of nucleotides/genes
- Products
- Inheritance pattern
- Circular, mtDNA
- 16,000 nucleotides encoding 13 proteins (many are subunits of protein complexes of the respiratory chain, 2 rRNA genes, and 22 tRNA genes)
- Almost entire genome is coding sequence
- Derived from oocyte mitochondria, thus they exhibit MATRILINEAL inheritance
- Affected female can pass disorder to ALL of her progeny
- Expression determined by degree of heteroplasmy
What is multfactorial/polygenic inheritance?
Disorders/traits that result from complex interactions between many or few genes and the environment
- Although the disorder/trait may be familial, there is NOT a simple mendelian pattern of inheritance
- Recurrence risks are based on empiric data
What does this pedegree show?
Multifactorial inheritance
Key concept: even without a positive family history we all have risks!
Examples, even in “normal” population:
- 1/30 risk of child being born with some congenital abnormality
- 1/50 risk of child being born with serious physical or mental handicap
- 1/8 risk of pregnancy ending with spontaneous abortion
In pedigrees, what shapes are used for:
- Males
- Females
- Unknown sex
- Miscarriage/abortion
- Males: square
- Females: circle
- Unknown sex: diamond
- Miscarriage/abortion: triangle
What does a slash through a shape indicate on a pedigree?
Deceased individual
What is the approach to genetic conditions with the physical exam?
- Head to toe: inspection
- Facial dysmorphisms (one thing alone may mean nothing)
- Obvious structural anomalies
- Fingers/toes
- Measurement of height, weight, and head circumference
What are different forms of genetic evaluation?
Chromosome/DNA level:
- Karyotype
- FISH
- Array CGH
Nucleotides
- Sequencing
- Single gene/panel
- Whole exome
What can be seen in a karytopye? What conditions?
- Abnormal number
- Down syndrome (3x21)
- Klinefelter syndrome (XXY)
- Turner (XO)
- Balanced translocation
- Big deletions/duplications
What is array CGH?
- Indications for it?
- Array Comparative Genomic Hybridization (Array CGH) allows for the detection of a large number of DNA copy number changes (gain/loss)
- Indications include: dysmorphic features; unexplained intellectual disability; autism spectrum disorder and/or multiple congenital anomalies
What is the process/mechanism of chromosomal microarray (CMA) or array CGH?
- What does Cy3/Cy5 > 1 indicate? < 1?
- Label pt DNA with Cy3 (green) and control with Cy5 (red)
- Mix should appear yellow
- Hybridize DNA to genomic clone microarray
- Analyze Cy3/Cy5 fluorescence ratio of patient to control
- Cy3/Cy5 > 1: duplication (more green)
- Cy3/Cy5 < 1: deletion (more red)
When is single gene testing helpful?
- Benefits?
- Phenotype and other findings clearly point to one disorder that is associated with one gene
- Ex) Marfan syndrome is associated only with the gene FBN1
- High clinical sensitivity
- Minimal risk of Variants of uncertain significance (VUS)
When are gene panels helpful?
- Benefits?
- Increases analytical sensitivity to DNA diagnostic testing
- Simplifies the decision making process for the ordering physician
- Number of genes for the same or similar clinical indications vary among different labs
- Is “more” better?
- Genes with a strong association are certainly included
- Genes associated with disorders that have overlapping phenotypes with those of the primary disorders are included for differential diagnosis
What is whole exome sequencing used for?
To analyze the exons or coding regions of thousands of genes simultaneously using next-generation sequencing techniques
- There are ~ 180,000 exons in the human genome, which represent about 3% of the genome and are arranged in about 22,000 genes
What is exome sequencing used for?
Exome sequencing is now the most commonly used tool for Mendelian disease gene discovery
- Diagnostic yield of 25%
- Significant cost-benefit for patients who remain undiagnosed after a few traditional appraoches
